p16iNK4a as a complementary marker of high-grade intraepithelial lesions of the uterine cervix. I: Experience with squamous lesions in 189 consecutive cervical biopsies

Dray, Michael; Russell, Peter; Dalrymple, Chris; Wallman, Neil; Angus, G. Elspeth; Leong, Adelyn; Carter, Jonathan; Cheerala, Bharathi

doi:10.1080/00313020500058607

Cited by 98 publications

(66 citation statements)

References 30 publications

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“…5), as compared to the keratinizing type carcinomas of the same site [6,7,22]. This immunohistochemical profile is analogous to that seen in HPV positive anogenital carcinomas [23][24][25]. As mentioned above the majority of oropharyngeal HPVrelated lesions start at the bottom of the crypts of the palatine and lingual tonsils, and thus are inaccessible to routine cytologic smears.…”

Section: Immunohistochemistrymentioning

confidence: 57%

Human Papillomavirus (HPV) Related Carcinomas of the Upper Aerodigestive Tract

El‐Mofty

2007

Head and Neck Pathol

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Epidemiologic, clinical, morphologic and molecular evidence show that high risk HPV, particularly type 16, is a prerequisite for some carcinomas of the upper aerodigestive tract (UADT), particularly tonsil and base of tongue. Sexual transmission is an important mode of infection while tobacco use and excessive drinking are not considered risk factors. HPV + tumors are distinct clinically and pathologically. They are more common in young patients (\40 years) with a male to female ratio of 4:1. They usually present as a small or occult primary tumor with advanced neck disease. Microscopically they are nonkeratinizing squamous cell carcinomas with basaloid features, excessive mitosis and comedo type necrosis. The tumors have a distinct immunohistochemical profile characterized by strong and diffuse p16 reactivity, low or negative p53 staining and high Ki67 labeling scores. HPV + carcinomas are more radio-sensitive and have a better prognosis than the classical keratinizing SCC of the UADT. An anti-HPV vaccine has recently been made available for prevention of cervical cancer. The impact of the vaccine on the prevalence of HPV related carcinomas of the UADT is currently not known but likely beneficial.Keywords Human papillomavirus Á HPV16 Á Upper aerodigestive tract Á Oropharynx Á Tonsils Á Base of tongue Á Non-keratinizing squamous cell carcinoma Á p16 Á Sexual transmission Á Radiosensitivity Á Vaccine Background

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Section: Immunohistochemistrymentioning

confidence: 57%

Human Papillomavirus (HPV) Related Carcinomas of the Upper Aerodigestive Tract

El‐Mofty

2007

Head and Neck Pathol

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“…In our study, we observed good correlation between p16 INK4A immunohistochemical staining and a consensus pathological diagnosis of CIN 2,31, consistent with what has been shown previously in the literature. 7,9,29 Using archival tissue we observed some heterogeneity of p16 INK4a staining in CIN 2,31, which may reflect either variations in the degree of overexpression of p16 INK4a within the lesions or variability in antigen retrieval. Lesions that were classified as CIN 2,31 on consensus pathology but that were p16 INK4A -negative had histological features suggestive of immature squamous metaplasia and did not recur after treatment.…”

Section: Discussionmentioning

confidence: 87%

“…In general, a strong association between finding high levels of p16 INK4a within a lesion by immunohistochemical staining and a diagnosis of CIN 2,3 has been found. 7,9,29 Immunohistochemical staining of cervical biopsies for p16 INK4a can reduce interobserver variation in their histolopathologic interpretation. 23 Moreover, women with cervical biopsies that are p16 INK4a -positive but not diagnosed as CIN 2,3 are at greatly elevated risk for subsequently being diagnosed with CIN 2,3 and women with p16 INK4a -negative CIN 1 lesions are less likely to progress to CIN 3 than those with p16 INK4a -positive CIN 1.…”

Section: Discussionmentioning

confidence: 99%

Impact of utilizing p16^INK4A immunohistochemistry on estimated performance of three cervical cancer screening tests

Zhang

Kuhn

Denny

et al. 2006

Intl Journal of Cancer

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The histopathological diagnosis of cervical intraepithelial neoplasia grade 2,3 (CIN 2,3) is subjective and prone to variability. In our study, we analyzed the impact of utilizing a biomarker (p16 INK4A ) together with histopathology to refine the ''gold standard'' utilized for evaluating the performance of 3 different cervical cancer screening tests: cervical cytology, human papillomavirus (HPV) DNA testing and visual inspection with acetic acid (VIA). Cervical biopsies from 2 South African cervical cancer screening studies originally diagnosed by a single pathologist were reevaluated by a second pathologist and a consensus pathology diagnosis obtained. Immunohistochemical staining for p16 INK4A was then performed. The estimated sensitivity of some cervical cancer screening tests was markedly impacted by the criteria utilized to define CIN 2,3. Use of routine histopathology markedly underestimated the sensitivity of both conventional cytology and HPV DNA testing compared to an improved gold standard of consensus pathology and p16 INK4A positivity. In contrast, routine histopathology overestimated the sensitivity of VIA. Our results demonstrate that refining the diagnosis of CIN 2,3 through the use of consensus pathology and immunohistochemical staining for p16 INK4A has an important impact on measurement of the performance of cervical cancer screening tests. The sensitivity of screening tests such as HPV DNA testing and conventional cytology may be underestimated when an imperfect gold standard (routine histopathology) is used. In contrast, the sensitivity of other tests, such as VIA, may be overestimated with an imperfect gold standard. ' 2006 Wiley-Liss, Inc. Key words: cervical intraepithelial neoplasia; p16 immunohistochemistryThe histolopathologic interpretation of cervical intraepithelial neoplasia (CIN) is subjective and prone to considerable variation. This is documented by numerous studies investigating intraobserver and interobserver variability among groups of pathologists evaluating cervical biopsies. [1][2][3][4] In general, agreement between pathologists is excellent for invasive lesions, moderately good for CIN 3 and poor for CIN 1 and CIN 2. 3 This results in marked difficulties in separating normal biopsies from CIN 1 and in distinguishing between CIN 1 and CIN 2,3 based on histopathology alone. 4 Recognition of this variability has led to concerted efforts to identify novel biomarkers capable of more reproducibly distinguishing between normal and CIN lesions and in reducing the variability in grading of CIN lesions. A number of potentially diagnostically useful biomarkers have been identified using conventional immunohistochemical approaches and tissue microarrays. 5-9 These include altered expression of selected MHC antigens; increased expression of Ki-67, telomerase and desmogleins and reduced expression of nm23-H1, a candidate tumor suppressor gene. [10][11][12][13][14] One of the more promising biomarkers is p16 INK4A , a cyclin-dependent kinase inhibitor involved in control of the cell ...

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“…This result probably represents the highest limit as compared to the findings of others. Intensive parabasal staining for p16 antigen was described in not more than 47% of CIN I cases, but continuous positive staining of lower intensity was reported in over 70% of CIN I cases [40,41]. Summing up the results of antigen p16 staining in the biopsy sections graded CIN I/LSIL, Yildiz et al [42] recognized continuous parabasal staining of high intensity, continuous parabasal staining of lower intensity and scattered staining of dispersed squamous epithelium cells.…”

Section: Overexpression Of the P16/ink4a Polypeptide In Hpv Transformmentioning

confidence: 99%

Diagnostic role of p16/INK4A protein in Human Papillomavirus (HPV) induced cervical dysplasia

Rajčáni¹,

Adamkov²,

et al. 2010

Open Life Sciences

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Abstract:The p16/INK4A protein is a cellular regulatory polypeptide over-expressed in the presence of high levels of the Human Papillomavirus (HPV) coded E7 protein. This review outlines the use of p16 antigen staining in cervical biopsies as well as in PAP smears summarizing the corresponding literature and commenting the authors' own experience. The p16 antigen is a reliable marker for dysplastic cells in CINII/CINIII (HSIL) lesions as viewed in cervical biopsies. When PAP smears were examined at large scale screening for p16 antigenreactive and atypical cells, considerable variations could be found especially in ASCUS graded lesions. Therefore, the presence of p16-reactive atypical cells in PAP smears should be interpreted together with the cytological signs of dysplasia, such as the altered N/C ratio. In addition, women revealing p16-positive ASCUS/LSIL specimens should be examined for the presence of HPV DNA. Detection of HPV DNA alone, i.e. in the absence of cytological screening has a low predictive value, since the clearance of HPV may occur even in the absence of morphological alterations. Combined cytological as well as molecular follow up contributes to the efficiency of diagnostic and increases the probability of correct interpretation of the pre-cancerous lesions by non-invasive techniques.

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p16iNK4a as a complementary marker of high-grade intraepithelial lesions of the uterine cervix. I: Experience with squamous lesions in 189 consecutive cervical biopsies

Cited by 98 publications

References 30 publications

Human Papillomavirus (HPV) Related Carcinomas of the Upper Aerodigestive Tract

Human Papillomavirus (HPV) Related Carcinomas of the Upper Aerodigestive Tract

Impact of utilizing p16^INK4A immunohistochemistry on estimated performance of three cervical cancer screening tests

Diagnostic role of p16/INK4A protein in Human Papillomavirus (HPV) induced cervical dysplasia

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p16iNK4a as a complementary marker of high-grade intraepithelial lesions of the uterine cervix. I: Experience with squamous lesions in 189 consecutive cervical biopsies

Cited by 98 publications

References 30 publications

Human Papillomavirus (HPV) Related Carcinomas of the Upper Aerodigestive Tract

Human Papillomavirus (HPV) Related Carcinomas of the Upper Aerodigestive Tract

Impact of utilizing p16INK4A immunohistochemistry on estimated performance of three cervical cancer screening tests

Diagnostic role of p16/INK4A protein in Human Papillomavirus (HPV) induced cervical dysplasia

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Impact of utilizing p16^INK4A immunohistochemistry on estimated performance of three cervical cancer screening tests